The adhesion of a living tissue occurs through its bonding to another tissue when the surface of a damaged organ is regenerated. Therefore, various adhesion barriers comprising a polysaccharide such as cellulose which is a biocompatible material are proposed to prevent adhesion after an operation.
For example, an adhesion barrier which is an aqueous solution of carboxymethyl cellulose is proposed (Am J Surg. 169, 154-159 (1995)). However, this adhesion barrier cannot exhibit an adhesion inhibition effect to the full due to its low retention properties in vivo.
Therefore, many attempts are being made to modify a polysaccharide by various methods or make it water-insoluble.
For example, adhesion barriers prepared by modifying hyaluronic acid and carboxymethyl cellulose with carbodiimide are proposed (JP-A 5-508161, JP-A 6-508169, Fertil Steril. 66. 904-910 (1996), J Am Coll Surg. 183, 297-306 (1996)). An adhesion barrier comprising a cellulose derivative obtained by substituting the hydrogen atom of cellulose with a specific substituent is further proposed (JP-A 1-301624). It is also proposed to use a composite material of carboxymethyl cellulose and a polyether as an adhesion barrier (U.S. Pat. Nos. 5,906,997, 6,017,301, 6,034,140). It is further proposed to use a cellulose derivative prepared by making soluble cellulose hardly soluble in water through an acid treatment as an adhesion barrier (WO01/34214 pamphlet). JP-A 2004-51531 proposes an adhesion barrier containing carboxymethyl cellulose which had been made hardly soluble in water. The adhesion barrier is substantially in a sponge or film form.
U.S. Pat. No. 5,064,817 discloses a reaction for obtaining a phospholipase A2 inhibitor composition by reacting carboxymethyl cellulose having a low molecular weight and phosphatidylethanolamine in a water solvent.
Not relating to an adhesion barrier, as means of chemically crosslinking a polysaccharide, it is proposed that carboxymethyl cellulose should be crosslinked by glyoxal (JP-A 10-251447). Further, a composition prepared by mixing carboxymethyl cellulose with a polyvalent metal ion is proposed (JP-A 63-37143). It is also proposed that hyaluronic acid should be crosslinked by bisepoxide (JP-A 7-97401). It is further proposed that hyaluronic acid should be crosslinked by divinyl sulfone (U.S. Pat. Nos. 4,582,865, 4,605,691). It is further proposed that hyaluronic acid should be crosslinked by formaldehyde or divinyl sulfone (JP-A 60-130601). JP-A 2003-518167 discloses a water-insoluble biocompatible gel prepared by reacting a polyanionic polysaccharide with an activator in an aqueous solution containing a water-compatible organic solvent and gives carboxymethyl cellulose as an example of the polyanionic polysaccharide.
All of the above proposals still have room to study as for adhesion preventing effect, handling properties and safety.